DESCRIPTION (Applicant's abstract):Diabetic dyslipidemia is associated with an increased risk of coronary vascular disease; therefore, factors affecting coronary vascular tone are major health concerns. Blood vessels in diabetic dyslipidemic animals frequently exhibit enhanced agonist-induced vasoreactivity. The overall hypothesis is that diabetic dyslipidemia alters the contribution of Ca2+ -activated K channels (KCa) channels to the maintenance of vascular tone resulting in increased vasoreactivity in the presence of an antagonist. Furthermore, exercise training will return KCa channel contribution to vascular tone towards healthy levels. KCa channel contribution to antagonist-induced contractions of coronary arteries in diabetic dyslipidemic (DF), exercise trained DF (DFX) and control (C) swine will be determined using endothelium denuded rings and freshly dispersed smooth muscle cells from the right coronary artery. Isometric tension recording in the presence of K channel blockers will be used to evaluate KCa and voltage dependent K channel contribution to antagonist-induced contractions. Electrophysiology, immunostaining and fluorescence microscopy will be used to investigate intrinsic KCa current characteristics, protein expression, and spatial organization of the KCa channel with the ryanodine-sensitive sarcoplasmic reticulum Ca2+ release channel. These studies will provide better understanding of the role KCa channels have in coronary conduit artery contraction. Additionally, these studies will help to determine whether endurance exercise training can be used as a therapeutic modality to regain normal KCa channel activity in diabetic dyslipidemia.